Comparison of RAS inhibitor classes for cerebrovascular management in hypertensive patients who contracted COVID-19 infection

Abstract. It has become increasingly clear that the cerebrovascular system is under assault in many individuals infected with COVID-19. In recent studies, patients with hypertension were found at a two-fold increased risk of dying from COVID-19 infection, and 100% of infected patients who received a magnetic resonance imaging (MRI) exam showed reduced CBF with 23% showing evidence indicative of ischemic stroke. The cerebrovascular dysregulation due to COVID-19 may add to the already enormous burden of stroke and dementia associated with age-related vascular deterioration. The pathogen SARS-CoV-2, causing COVID-19 illness, is now known to reduce function of an enzyme termed ACE2 that is a major regulator in the Renin- Angiotensin system (RAS) that controls blood pressure and cerebral blood flow (CBF). This SARS-CoV-2 pathophysiology might lead to excessive stimulation of type 1 angiotensin receptor (AT1R) but reduced stimulation of type 2 angiotensin receptor (AT2R), which is likely to both exacerbate hypertension and disrupt CBF autoregulation and neurovascular coupling. Fortunately, two classes of currently available antihypertensive medications are designed to regulate RAS by inhibiting AT1R. However, there may be a critical difference between these two classes. Angiotensin II receptor blockers (ARBs) are protective of the pro-CBF activity on the AT2R, and thus may be more effective at preventing the cerebrovascular dysregulation than the other class, inhibitors of an enzyme termed ACE (ACEIs), which inhibit AT2R activity. The goal of this R21 research proposal is to compare the effectiveness of ARB and ACEI antihypertensive medicines in preventing long-term cerebrovascular dysregulation in hypertensive patients infected with COVID- 19. Two novel imaging methods recently developed in our lab will be leveraged to assess CBF autoregulation and neurovascular coupling (NVC) at least 1 year after the severe infection. First, we will conduct noninvasive optimized arterial spin labeling (ASL) MRI and respiratory challenge-weighted blood oxygenation level- dependent (BOLD) MRI to measure baseline CBF and autoregulatory capacity in combination with novel analyses that decouple the magnitude of vascular signal from contamination due to timing-related differences. Second, we will acquire simultaneous resting-state electroencephalogram and BOLD MRI to estimate the body's capacity to adjust vascular energy delivery in response to changes in the demand from neural electrophysiological activity. We will quantify this NVC with cutting-edge mathematical analysis that detects transient states of network activity in EEG and models the time-concordant local BOLD MRI responses. Successful implementation of this approach would offer sensitive measurement of CBF regulation in hypertensive COVID-19 survivors and would indicate that one class of antihypertensive medication may be more effective in CBF management in the face of COVID-19-related dysregulation, demonstrating urgency of clinical trials of RAS inhibitors in hypertensive patients with COVID-19 to optimize future clinical care.